Circular DNA-driven cancer genome remodeling

Projektinformationen

CancerCirculome

ID Finanzhilfevereinbarung: 949172

DOI

10.3030/949172

Projekt abgeschlossen

EK-Unterschriftsdatum 8 Dezember 2020

Startdatum 1 Februar 2021

Enddatum 31 Januar 2026

Finanziert unter

• EXCELLENT SCIENCE - European Research Council (ERC)

Gesamtkosten

€ 1 498 888,00

EU-Beitrag

€ 1 498 888,00

Koordiniert durch

CHARITE - UNIVERSITAETSMEDIZIN BERLIN
Germany

Periodic Reporting for period 4 - CancerCirculome (Circular DNA-driven cancer genome remodeling)

Berichtszeitraum: 2025-08-01 bis 2026-01-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

CancerCirculome addressed a fundamental gap in our understanding of how cancers evolve and develop resistance to therapy. While most cancer research has focused on mutations within chromosomes, this project investigated an alternative and less understood mechanism: the role of extrachromosomal circular DNA (ecDNA), which can carry cancer-driving genes outside of chromosomes.
Over the course of the project, we established that ecDNA is not only a frequent feature of cancer genomes but also a dynamic driver of tumor evolution. We showed that ecDNA contributes to therapy resistance by enabling cancer cells to rapidly change the number of oncogenes they carry, without requiring new mutations.
The overall objective of CancerCirculome was to understand how ecDNA is formed, how it is maintained in cells despite lacking normal chromosomal structures, how it influences gene regulation and tumor behavior, and how it can be exploited clinically. These objectives were addressed through the development of new technologies, mechanistic studies of ecDNA biology, and translational approaches.
By the end of the project, CancerCirculome has established ecDNA as a central mechanism of cancer genome remodeling and adaptation. The findings provide a foundation for new diagnostic tools and therapeutic strategies aimed at targeting ecDNA-driven cancers, with potential relevance for a wide range of tumor types.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

Over the full duration of CancerCirculome, we made substantial progress in understanding the structure, function, and clinical relevance of extrachromosomal circular DNA.
First, we developed a suite of new technologies to study ecDNA, including computational methods for reconstructing complex circular DNA structures from sequencing data (DeCoil), and a single-cell sequencing method (scEC&Tseq) that allows simultaneous analysis of ecDNA and gene expression. These tools enabled us to map ecDNA architecture and heterogeneity at unprecedented resolution.
Using these approaches, we demonstrated that ecDNA is highly heterogeneous across cancer cells and is inherited in a non-Mendelian manner, generating rapid variability in oncogene copy number. We further showed that ecDNA can form spatial clusters (“ecDNA hubs”) within the nucleus, enabling cooperative regulation of oncogenes.
Importantly, we established that ecDNA is a dynamic driver of therapy resistance. Cancer cells can increase or decrease ecDNA copy number under treatment pressure, allowing rapid adaptation without requiring genetic mutations. This reveals a new mechanism of tumor evolution.
In the final phase of the project, we uncovered mechanisms that explain how ecDNA is maintained in dividing cells, identified its three-dimensional organization using new computational approaches (ec3D), and demonstrated that circular DNA can also contribute to tumor-promoting processes such as inflammation.
Finally, we translated these findings into clinical applications by developing liquid biopsy approaches that detect tumor-specific circular DNA features in patient blood, enabling improved disease monitoring.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

CancerCirculome has significantly advanced the field beyond the state of the art by transforming our understanding of extrachromosomal circular DNA from a poorly characterized genomic feature into a central driver of cancer evolution.
At the start of the project, ecDNA was primarily considered a static form of oncogene amplification. Our work demonstrated that ecDNA is highly dynamic, structurally complex, and unevenly inherited, enabling rapid changes in oncogene dosage within tumor cell populations. This provides a fundamentally new explanation for how cancers adapt quickly to therapy.
Several key discoveries were unexpected. We found that small circular DNAs are largely not propagated between cells, in contrast to large oncogene-containing ecDNA, leading to a refined understanding of which circular DNA species are functionally relevant. We also contributed to the discovery of ecDNA hubs, revealing that circular DNA can reorganize the three-dimensional structure of the genome to regulate gene expression.
In the final phase of the project, we identified mechanisms that enable ecDNA to persist in cells, reconstructed its three-dimensional architecture, and showed that circular DNA can promote tumor development through mechanisms beyond gene amplification, including inflammatory signaling.
Overall, CancerCirculome establishes ecDNA as a dynamic and functionally important layer of genome organization and tumor evolution. These advances open new avenues for research and provide a conceptual framework for developing future diagnostic and therapeutic strategies targeting ecDNA.

FISH of ecDNA in neuroblastoma cells.